Intermediate for preparing midodrine

ABSTRACT

The invention provides a process for the preparation of 2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide of the formula 1 by hydrogenolysis of substituted 2-dibenzylamino-N-[2-(2′,5′-dimethoxyphenyl)-2-hydroxy-ethyl]acetamide having the formula (5), wherein Ar and Ar′are aryl groups.

[0001] The present invention is related to a novel process for thepreparation of2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamidehydrochloride, also known as Midodrine hydrochloride, having thefollowing formula (1).

BACKGROUND OF THE INVENTION

[0002] Midodrine is classified as an antihypotensive drug. It was firstdescribed and claimed in the U.S. Pat. No. 3,340,298 The drug isdispensed in tablet form as the hydrochloride salt having the structure(1). The key intermediate required for preparing Midodrine is1-(2,5-dimethoxy-phenyl)-2-aminoethanol hydrochloride having thestructure (2).

[0003] The synthesis of Midodrine HCl consists of reacting the keyintermediate (2) with chloroacetyl chloride to afford2-chloro-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide (3). Thereaction of (3) with sodium azide will provide2-azido-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide (4) which issubsequently subjected to hydrogenation to afford Midodrine base (6).

[0004] Acidification with aqueous HCl will provide Midodrine HCl (1).The above sequence of reactions are outlined in the following scheme(see for example Austrian patent AT 336584).

[0005] A serious drawback in the above synthesis of Midodrine HClinvolves the use of the dangerously explosive sodium azide. In addition,the above synthesis will involve the formation of the organic azide (4),which is also a potentially explosive material. Both sodium azide andthe azide (4) are also toxic materials.

[0006] The development of a process for Midodrine HCl, which avoids theuse of the highly toxic and explosive sodium azide, will be of greatbenefit.

SUMMARY OF THE INVENTION

[0007] According to the present invention, a process is now availablefor the preparation of Midodrine hydrochloride (1) via a safe process.In addition, all of the intermediates involved in the preparation of (1)are safe to handle In the present invention, the toxic and potentiallyexplosive sodium azide is replaced by a safe to handle bis (substituted)diaryl amine, preferably dibenzylamine. The new synthesis of MidodrineHCl consists of reacting 1-(2,5-dimethoxy-phenyl)-2-aminoethanolhydrochloride (2) with chloroacetyl chloride in a mixture of methylenechloride and aqueous potassium hydroxide solution at 5°-10° C. toproduce 2-chloro-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]-acetamide(3).

[0008] The chloro acetamide derivative (3) is not isolated but reactedin situ, after removal of the methylene chloride, with a bis(substituted) diarylamine having formula (6) in refluxing toluene for aperiod of about 10 hours. Ar and Ar′ groups in formula (6) areindependently phenyl or substituted phenyl groups. The substituents canbe chosen from C₁-C₄ alkyl groups, C₁-C₄ alkoxy groups, C₁-C₄dialkylamino groups and halo groups. The preferred amine of formula (6)is dibenzyl amine of formula (8) wherein both Ar and Ar′ groups arephenyl groups The product,2-(substituted)-dibenzylamino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide(5) is isolated by filtration. In the next step, the intermediate (5) ishydrogenolyzed to give Midodrine free base (9). The hydrogenolysis isperformed at 40°-70° C., preferably 50° C., and 4-6 bar hydrogenpressure using 5% Pd/C as catalyst. The reaction is performed in analcoholic medium, preferably ethanol. After removal of the alcohol, theMidodrine base (9) is isolated by filtration.

[0009] In the final step, the Midodrine base (9) is dissolved inethanol. The addition of a solution of HCl gas in isopropanol causes thehydrochloride salt of Midodrine to separate from solution. A filtrationwill afford Midodrine HCl (1) in a highly pure form.

[0010] It should be pointed out that all of the reagents as well as theintermediates involved in the process can be safely handled and provideno safety risks. The above sequence of reactions is outlined in thefollowing scheme.

[0011] While the invention will now be described in connection withcertain preferred embodiments in the following examples so that aspectsthereof may be more fully understood and appreciated, it is not intendedto limit the invention to these particular embodiments. On the contrary,it is intended to cover all alternatives, modifications and equivalentsas may be included within the scope of the invention as defined by theappended claims. Thus, the following examples which include preferredembodiments will serve to illustrate the practice of this invention, itbeing understood that the particulars shown are by way of example andfor purposes of illustrative discussion of preferred embodiments of thepresent invention only and are presented in the cause of providing whatis believed to be the most useful and readily understood description offormulation procedures as well as of the principles and conceptualaspects of the invention.

EXAMPLES Example 1

[0012] Preparation of 2-chloro-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide

[0013] The reaction vessel is charged with 15.5 g1-(2,5-dimethoxyphenyl)-2-amino-ethanol hydrochloride, 115 ml methylenechloride and 100 ml water. The mixture is stirred at 25°-30° C. toafford a clear two-phase mixture. The mixture is cooled to 5°-10° C. anda solution of 18.7 g of 50% potassium hydroxide and 18.5 ml water isadded in portions at 5°-10° C.

[0014] The mixture is stirred at 5°-10° C. for 15 min. 8.0 ml ofchloroacetyl chloride is added in portions at 5°-10° C. causing anexothermic reaction to occur. On completion of the addition, the pHshould be adjusted to 3-6. The mixture is allowed to warm to 25°-30° C.and the pH is adjusted again to 3-6. After stirring for one hour at25°-30° C., the pH is adjusted to 6-7 with 5% aqueous potassiumhydroxide solution. The stirring is stopped and the layers areseparated.

[0015] The upper aqueous layer is washed with 25 ml of methylenechloride. The organic layers are combined and dried over magnesiumsulfate. The solution of2-chloro-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide inmethylene chloride is used as is in the next step.

Example 2

[0016] Preparation of2-dibenzylamino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide

[0017] The reaction vessel is charged with the methylene chloridesolution of 2-chloro-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamideprepared in example 1. The majority of the methylene chloride isdistilled off at atmospheric pressure. On completion of the distillation155 ml toluene are added. The mixture is stirred to obtain a solution.45 to 50 ml of the toluene is distilled to remove the remainder ofmethylene chloride. The mixture is cooled to 85°-90° C. and 28.4 gdibenzylamine is added in portions at 85°-90° C. On completion of theaddition, the mixture is heated to reflux for a period of 10 hours.

[0018] On completion of reaction, the resulting suspension is cooled to45°-50° C. 110 ml water are added followed by 7.5 g of 50% potassiumhydroxide. The mixture is stirred at 25°-30° C. for a period of 2-3hours during which time the product crystallizes from solution. Aftercooling to 5°-10° C., the product is filtered to afford 21.7 g of2-dibenzylamino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide.This represents a 75% yield based on the starting material fromexample 1. The product is characterized as follows:

[0019] m.p.: 110.0-111.1° C.

[0020] MS: 434 (M⁺)

[0021]¹H-NMR (DMSO-d₆): 7.65 ppm, triplet, J=6 Hz, CH₂—NH, 1H; 7.35-7.26ppm, multiplet, benzyl aromatic protons, 1OH; 7.06-6.81 ppm, multiplet,dimethoxy aromatic protons, 3H; 5.60 ppm, doublet, J=5 Hz, CH—OH, 1H;4.95 ppm, multiplet, CH—OH, 1H; 3.71 and 3.65 ppm, two singlets, two OCH₃, 6H; 3.54 ppm, broad singlet, two CH ₂—Ph, 4H; 3.36 ppm, singlet, H₂O; 3.45 and 3.15 ppm, two multiplets, CH ₂—NH, 2H; 2.93 ppm, broadsinglet, CH ₂—N, 2H.

[0022]¹³C-NMR (DMSO-d₆): 169.62 ppm, C₁₁; 153.19+149.82 ppm, C₁+C₄;138.21 ppm, C₁₅/C₂₁; 132.26 ppm, C₆; 128.78 ppm, C₁₆/C₂₀/C₂₂/C₂₆; 128.31ppm, C₁₇/C₁₉/C₂₃/C₂₅; 127.14 ppm, C₁₈/C₂₄; 112.79+112.25+111.59 ppm,C₂+C₃+C₅; 65.49 ppm, C₉; 57.72 ppm, C₁₃/C₁₄; 56.45 ppm, C₁₂; 55.80+55.18ppm, C₇+C₈; 44.38 ppm, C₁₀.

Example 3

[0023] Preparation of2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide (MidodrineBase)

[0024] An autoclave is charged with 15.0 g of2-dibenzylamino-N-[2-(2,5-dimethoxy-phenyl)-2-hydroxyethyl]acetamide,200 ml ethanol and 1.5 g of 5% Pd/C catalyst. The system is flushedthree times with nitrogen followed by hydrogen. The pressure of hydrogenis adjusted to 4-6 bar. The temperature is adjusted to 45°-50° C. Themixture is stirred and heated at 45°-50° C. for 24 hours.

[0025] On reaction completion, the mixture is cooled to 25°-30° C. andfiltered through a Celite pad to separate the catalyst. The clearf/Uiltrate is transferred to a clean reaction vessel. About ½ of theethanol is distilled out at atmospheric pressure. On cooling andseeding, Midodrine base will crystallize from solution. After cooling to5°-10° C., the product is filtered to afford 6.3 g (71% yield) of whiteMidodrine base. The product is characterized as follows:

[0026] m.p.: 105.8°-106.8° C.

[0027] MS: 254 (M⁺)

[0028]¹H-NMR (DMSO-d₆): 7.88 ppm, triplet, J=6 HZ, CH₂—NH, 1H; 7.02-6.76ppm, multiplet, aromatic protons, 3H; 5.42 ppm: broad singlet, CH—OH,1H; 4.90 ppm, multiplet, CH—OH, 1H; 3.73+3.70 ppm, two singlets, two OCH₃, 6H; 3.45+3.01 ppm, two multiplets, CH ₂—NH, 2H; 3.06 ppm, broadsinglet, CH ₂—NH₂, 2H.

[0029]¹³C-NMR (DMSO-d₆): 172.75 ppm, C₁₁; 153.11+149.65 ppm, C₁+C₄;132.45 ppm, C₆; 112.53+112.17+111.48 ppm, C₂+C₃+C₅; 65.64 ppm, C₉;55.74+55.18 ppm, C₇+C₈; 44.82+44.54 ppm, C₁₀+C₁₂.

Example 4

[0030] Conversion of Midodrine Base to Midodrine Hydrochloride

[0031] The reaction vessel is charged with 5.0 g Midodrine base and 60ml ethanol. The mixture is heated to reflux to obtain a clear solution.To the hot mixture is added 6.3 ml of a 22% solution of hydrochloricacid in isopropanol in portions. During the addition, the Midodrine HClwill crystallize from solution. After cooling to 5°-10° C., the productis filtered to afford 4.8 g (96% yield) of Midodrine HCl (m.p.:200.8°-201.8° C.).

[0032] It will be evident to those skilled in the art that the inventionis not limited to the details of the foregoing illustrative examples andthat the present invention may be embodied in other specific formswithout departing from the essential attributes thereof, and it istherefore desired that the present embodiments and examples beconsidered in all respects as illustrative and not restrictive,reference being made to the appended claims, rather than to theforegoing description, and all changes which come within the meaning andrange of equivalency of the claims are therefore intended to be embracedtherein

What is claimed is:
 1. A process for the preparation of2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide of theformula 1 by hydrogenolysis of substituted2-dibenzylamino-N-[2-(2′,5′-dimethoxyphenyl)-2-hydroxy-ethyl]acetamidehaving the formula (5), wherein Ar and Ar′ are aryl groups.


2. A process according to claim 1 in which the compound of formula (5)is prepared by reacting2-chloro-N-[2-(2,5-dimethoxyphenyl)-2-hydroxy-ethyl]acetamide of formula(3) with a substituted dibenzylamine of the formula (6).

ArCH₂NHCH₂Ar′  6 wherein Ar and Ar′ are optionally substituted phenylgroups.
 3. A process according to claim 2 wherein the aryl ar and ar′groups are indipendtly phenyl or substituted phenyl groups wherein thesesubstituents are chosen from C₁-C₄ alkyl groups, C₁-C₄ alkoxy groups,C₁-C₄ dialkylamino groups and halo groups.
 4. A process according toclaim 3 wherein both Ar and Ar′ groups in formula (6) are phenyl groups.5. A process according to claim 1 wherein the hydrogenolysis reaction isdone by hydrogen over a palladium on carbon catalyst
 6. A processaccording to claim 3 wherein the hydrogen pressure is between 4-6 bars.7. A process according to claims 3 and 4 wherein the reactiontemperature is between 40°-70° C.
 8. A process according to claims 3,4and 5 wherein the reaction medium is an alcohol of the formula ROH inwhich R is a C₁-C₄ alkyl group.
 9. A process according to claim 6wherein the reaction medium is ethanol. 10.2-dibenzylamino-N-[2-(2′,5′-dimethoxyphenyl)-2-hydroxyethyl]-acetamidehaving the formula (7).